progeria

progeria

[proh-jeer-ee-uh]

Disorder with characteristics of premature aging. Affected persons have thin skin, go bald or gray early, and develop diseases of aging decades earlier than normal individuals. Not all systems are affected; there is no senility, no aging in the central nervous system. There are two major types. In the extremely rare Hutchinson-Gilford syndrome, children look 60 years old by age 10 and die at an average age of 13. The unrelated Werner syndrome is a recessive hereditary disease that begins in young adulthood and makes patients look 30 years older than they are; their average life span is 47 years.

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Progeria is a condition of early aging which usually refers specifically to Hutchinson-Gilford Progeria syndrome.

Hutchinson-Gilford Progeria syndrome is an extremely rare condition in which physical aspects of aging are greatly accelerated, and few affected children live past age 13. About 1 in 8 million babies are born with this condition. It is a genetic condition, but occurs sporadically and is usually not inherited in families.

Scientists are particularly interested in progeria because it might reveal clues about the normal process of aging.

Symptoms

The earliest symptoms include failure to thrive (FTT) and a localized scleroderma-like skin condition. As the child ages past infancy, additional conditions become apparent. Limited growth, alopecia, and a distinctive appearance with small face and jaw and pinched nose all are characteristic of progeria. The people diagnosed with this disease usually have small, fragile bodies like those of elderly people.

Later the condition causes wrinkled skin, atherosclerosis and cardiovascular problems.

Cause

Hutchinson-Gilford Progeria Syndrome (HGPS) is a childhood disorder caused by mutations in one of the major architectural proteins of the cell nucleus. Unlike most other "accelerated aging diseases" (such as Werner's syndrome, Cockayne's syndrome or xeroderma pigmentosum), progeria is not caused by defective DNA repair. Because these "accelerated aging" diseases display different aspects of aging, but never every aspect, they are often called "segmental progerias".

Diagnosis

Diagnosis is suspected according to signs and symptoms, such as skin changes, abnormal growth, and loss of hair. It can be confirmed through a genetic test.

Treatment

No treatments have been proven effective. Most treatment focuses on reducing complications such as cardiovascular disease, such as heart bypass surgery or low-dose aspirin. Children may also benefit from a high-calorie diet.

Growth hormone treatment has been attempted.

A type of anti-cancer drug, the farnesyltransferase inhibitors (FTIs), have been proposed, but their use has been mostly limited to animal models. A phase II clinical trial using the FTI Lonafarnib began in May 2007.

Prognosis

There is no known cure. Few people with progeria exceed 13 years of age. At least 90% of patients die from complications of atherosclerosis, such as heart attacks or strokes.

Mental development is not affected. The development of symptoms is comparable to aging at a rate six to eight times faster than normal, although certain age-related conditions do not occur. Specifically, patients show no neurodegeneration or cancer predisposition. They also do not develop "wear and tear" conditions commonly associated with aging, like cataracts and osteoarthritis.

Epidemiology

One study from the Netherlands has shown an incidence of 1 in 4 million births. Currently, there are 48 known cases in the world.

Approximately 100 cases have been formally identified in medical history.

Classical Hutchinson–Gilford Progeria Syndrome is not passed on from parent to child, because most affected children don't live long enough to have children themselves. It is usually caused by a new (sporadic) mutation during the division of the cells that create unfertilized egg or sperm.

Hutchinson–Gilford Progeria Syndrome is genetically dominant, therefore parents who are healthy cannot pass it on to their children.

However, there are milder cases in which either the gene is not expressed in parents, or a different gene is responsible for a different form of progeria, and healthy parents can pass on their children.

Three families have been identified as having more than one child with the disease. The first was a family in India that has five children with progeria, two of which are now deceased. The eldest daughter with progeria is 19 years old, and their eldest son with progeria is 17, both having survived longer than typical among people with progeria. Their other living child with progeria is 7. The family was a subject of a 2005 Bodyshock documentary entitled The 80 Year Old Children.

In 2006, the Vandersweets, a family in Belgium, who already had one child diagnosed with progeria, were informed that their second child also had the disease.

The third case is a family that lives in Aguacatan in Guatemala. The family consists of 3 children. 1, 7 and 18 years old. The 7 and 18 year old both have been diagnosed with Progeria. Status of the infant is still uncertain.

Research areas

Several discoveries have been made that have led to greater understanding and perhaps eventual treatment.

A 2003 report in Nature said progeria may be a de novo dominant trait. It develops during cell division in a newly conceived child or in the gametes of one of the parents. It is caused by mutations in LMNA (Lamin A protein) gene on chromosome 1; The mutated form of Lamin A is commonly known as progerin. One of the authors, Leslie Gordon, was a physician who didn't know anything about progeria, until her own son, Sam, was diagnosed at 21 months. Gordon and her husband, pediatrician Scott Berns, founded the Progeria Research Foundation.

Lamin A

Nuclear lamina is a protein scaffold on the inner edge of the nucleus that helps organize nuclear processes such as RNA and DNA synthesis.

Prelamin A contains a CAAX box at the C-terminus of the protein (where C is a cysteine and A is any aliphatic amino acids). This ensures that the cysteine is farnesylated, and this allows Prelamin A to bind membranes, specifically the nuclear membrane. After Prelamin A has been localized to the cell nuclear membrane the C-terminal amino acids, including the farnesylated cysteine, are cleaved off by a specific protease. The resulting protein is now Lamin A, is no longer membrane-bound and carries out functions inside the nucleus.

In HGPS the recognition site that the enzyme requires for cleavage of Prelamin A to Lamin A is mutated. Lamin A cannot be produced and Prelamin A builds up on the nuclear membrane, causing a characteristic nuclear blebbing. This results in the premature aging symptoms of progeria, although the mechanism connecting the misshapen nucleus to the symptoms is not known.

A study which compared HGPS patient cells with the skin cells from LMNA young and elderly human subjects found similar defects in the HGPS and elderly cells, including down-regulation of certain nuclear proteins, increased DNA damage and demethylation of histone leading to reduced heterochromatin. Nematodes over their lifespan show progressive lamin changes comparable to HGPS in all cells but neurons and gametes. These studies suggest that lamin A defects contribute to normal aging.

Mouse model of progeria

A mouse model of progeria exists, though in the mouse the LMNA prelamin A is not mutated, but instead ZMPSTE24, the specific protease that is required to remove the C-terminus of Prelamin A is missing. Both cases result in the build up of farnesylated Prelamin A on the nuclear membrane and in the characteristic nuclear LMNA blebbing. Fong et al use a farnesyl transferase inhibitor (FTI) in this mouse model to inhibit protein farnesylation of Prelamin A. Treated mice had greater grip strength, lower likelihood of rib fracture and may live longer than untreated mice.

This method does not directly 'cure' the underlying cause of progeria. This method prevents Prelamin A going to the nucleus in the first place so no Prelamin A can build up on the nuclear membrane, but equally there is no production of normal Lamin A in the nucleus. Luckily Lamin A does not appear to be essential, indeed mouse models in which the genes for Prelamin A and C are knocked out show no symptoms. This also shows that it is the build up of Prelamin A in the wrong place, rather than the loss of the normal function of Lamin A that causes the disease.

It was hypothesized that part of the reason that treatment with an FFI such as alendronate is inefficient due to prenylation by geranylgeranyltransferase. Since statins inhibit geranylgeranyltransferase, the combination of an FFI and statins was tried, and markedly improved "the aging-like phenotypes of mice deficient in the metalloproteinase Zmpste24, including growth retardation, loss of weight, lipodystrophy, hair loss and bone defects".

History

Progeria was first described in 1886 by Jonathan Hutchinson and also described independently in 1897 by Hastings Gilford. The condition was later named Hutchinson-Gilford Progeria syndrome (HGPS).

Cultural references

  • The character J.F. Sebastian in the 1982 movie Blade Runner suffers from "Methuselah syndrome", a fictional equivalent of progeria.
  • The character Orlando Gardiner in the Otherland series of four books by Tad Williams suffers from progeria.
  • In the play, Kimberly Akimbo, the character Kimberly Levaco has progeria.
  • In the movie Renaissance, a science fiction speculation is made on progeria as the holy grail for the discovery of the genetic key to immortality.
  • In the TV series Strange a demon called Zoxim is said to cause rapid aging through the progeria.
  • In the novel Haunted, the character Brandon Whittier suffers from progeria.
  • In the television series The X-Files episode Young At Heart the plot involves a doctor working on patients with progeria.
  • The main character in the movie Jack (film) has an fake and exaggerated form of progeria, with Jack aging four times faster than usual, but otherwise normally. That is, he looks exactly like a 40 year old man at age 10.
  • Experiments gone wrong lead to an extremely accelerated form of progeria in the new 2008 TV series FRINGE.

See also

References

External links

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